How information is routed to the neocortex as a function of behavioral state is a fundamental but poorly understood question in modern neuroscience. The thalamic reticular nucleus (TRN) is an inhibitory structure that is hypothesized to gate information throughput from thalamus to cortex, but experimental evidence clarifying the details of this process is lacking. To overcome these limitations, interrogate intac TRN microcircuits and understand their role in behavior we will create novel molecular tools that confer genetic targeting specificity to this brain structure Aim I. Using innovative genome editing technologies, we will maximize targeting success, while minimizing the time taken to validate these tools. Using these tools, we will ask how TRN microcircuits are functionally organized addressing how the thalamus may differentially gate multiple competing inputs to guide behavioral output, Aim II. In addition to opening several venues for further basic understanding of brain microcircuits, state regulation and cognition, this research will be of tremendous translational impact. In a parallel collaboration between Halassa and Feng, we are studying a mouse model of monogenic human autism with a primary TRN dysfunction. The genetic methods we are creating will equip us with the ability to develop molecular and optical interventional tools for treatment of this disorder and other neurodevelopmental diseases.